This project has the long-term objective of improving our understanding of the pathogenesis of nephrolithiasis in man by studying nephrolithiasis in the rat. Idiopathic hypercalciuria in man is associated with an increased risk of nephrolithiasis. We have successfully bred a colony of genetic hypercalciuric stone forming (GHS) rats, not in their 51st generation, whose daily urinary calcium excretion (Uca) is approximately 9-10 times that of controls. As in man with idiopathic hypercalciuria, intestinal calcium (Ca) absorption exceeds that of normal rats. When the GHS rats are fed a diet almost devoid of Ca their Uca exceeds that of controls and exceeds dietary Ca intake indicating that enhanced bone demineralization contributes to the hypercalciuria in this setting. There is greater net Ca efflux from bone (calvariae) of neonatal GHS rats cultured in medium containing 1,25(OH)2D3 compared to control calvariae and administration of alendronate, an inhibitor of bone resorption, decreases hypercalciuria on a low Ca diet. Metabolic clearance studies indicate a defect in renal Ca reabsorption in the GHS rats. Thus the mechanisms of the increased Uca appears to be increased intestinal Ca absorption in addition to a component of decreased renal Ca reabsorption in the GHS rats. Thus the mechanism of the increased UCa appears to be indicate a defect in renal Ca reabsorption in the GHS rats. Thus the mechanism of the increased UCa appears to be increased intestinal Ca absorption in addition to a component of decreased renal Ca reabsorption and enhanced bone mineral resorption suggesting a systemic disorder of Ca regulation. The female GHS rats have greater urinary supersaturation (SS) with respect to brushite (CaHPO4) and have a greater kidney Ca content than either normocalciuric females or males or GHS males. After eating standard rat chow (1.2% Ca) for 18 weeks 100% of the female GHS rats formed renal stones while there was no evidence of stone formation in controls. By x-ray diffraction all stones are identified as a poorly crystalline apatite, a Ca phosphate complex. With increasing dietary Ca there is an increase in the upper limit of metastability (ULM) with increasing SS for Ca oxalate (Ox), but not brushite. Thus our GHS rats appear to be an excellent model of human idiopathic hypercalciuria. We propose to: 1) Test the hypothesis that the degree of urine supersaturation in relation to the upper limit of metastability determines the solid phase of the stone formed. 2) Test the hypothesis that the increase in the upper limit of metastability with increasing CaOx supersaturation is due to an increase in inhibitor activity. 3) Test the hypothesis that the site of initial stone formation is the descending limb of Nenle's loop.